This proposal investigates the mechanism underlying the clinical manifestations of baroreflex failure and of baroreflex dysfunction. The Vanderbilt Autonomic Dysfunction Center provides a unique resource of patient referrals with baroreflex failure. This includes patients with the familial paraganglioma syndrome; which leads to predictable bilateral carotid sinus deafferentation. In addition, the sporadic unilateral form of this disorder will allow us to assess the laterality of effects. We will test the hypothesis that the pathologic decrease in vagal afferent activity in these patients alters the activity of multiple cortical and sub-cortical areas, by comparing in normal volunteers and in patients using electrical cervical vagal stimulation for the treatment of seizures the hemodynamic responses to discrete cortical stimuli (visual, auditory, taste and nociceptive stimuli, Stroop testing and mental arithmetic), the response of vasopressin, and autonomic activation with spectral analysis of blood pressure and heart rate and plasma catecholamines as well as defining the functional level of specific brain receptor fields. We will define mechanisms supporting orthostatic blood pressure in these patients, specifically by testing the effect of vestibular input with differential tilt studies. In a separate series of studies of baroreflex dysfunction, we will test the hypothesis that variable levels and durations of acute and chronic glycemic control alter baroreflex function in diabetics, utilizing direct assessment of baroreflex function, and blood and plasma volume determination during insulin clamp studies. We will also define the effect of carotid endarterectomy or stenting on baroreflex function and utilize carotid ultrasound to evaluate the role of the mechanical/vascular component. We will further assess the hypothesis that therapeutic options of demonstrated utility either in pilot studies of baroreflex failure and/or in patients with other forms of automomic dysfunction (e.g., clonidine, oral water, citrulline, and modulation of prostaglandin synthesis) are effective in patients with baroreflex dysfunction or failure. The data derived from these studies will provide important information that should lead to improve treatment for these patients.